Thursday, 21st June 2018

Molecular Neuropathology

    Biology of human neural stem cells. Potential for cell                                                                                               and gene therapy in neurodegeneration




Alberto Martínez Serrano




Research summary:

The incidence of neurodegenerative diseases is steadily increasing, particularly in well-developed countries, due to the increase in life expectancy. For some of them, like Parkinson, Huntington diseases, pharmaceutical drugs are useful at early stages of the disease, but none of them really cure the disease, since they do not halt the neuronal atrophy and death process.

In this context, research on the basic biology of human neural stem cells acquires special relevance, with the prospect that healthy stem cell derivatives, after implantation, would either delay disease progression or actually cure the disease.

Our research group is interested in understanding basic self-renewal (niche factors) and developmental events leading to maturation of stem cell derivatives, using: 1) Neural stem cells, obtained from foetal or adult human tissue, and thus instructed as neural cells; 2) Embryonic stem cells derived from the inner cell mass of the blastocist, (hES cells) from which neural stem cells can be derived; and 3) Induced pluripotent stem cells (iPSCs), reprogrammed from somatic adult cells.

Fig01-300 ..... Generation of human dopaminergic neurons from neural stem cells.
Top panels are microphotographs of human neurons generated in culture, stained for a general neuronal marker (ß-III-tubulin, green) and Tyrosine Hydroxylase (dopaminergic marker, red). The lower panel is a merge of the two photographs, highlighting in yellow the presence of human dopaminergic neurons.

Our main research focus is thus on basic cell growth and developmental events involved in the generation of mature cells, particularly of Dopaminergic neurons, to learn how to harness the potential that stem cells may have for therapy of these devastating diseases.

Another aspect in which we are interested on is the modification of the intrinsic properties of the neural stem cells through genetic modification, to turn them into "biological mini-pumps" (for instance for the secretion of neurotrophic factors), or to instruct them or guide their differentiation towards specific, on-demand desired phenotypes after implantation. To this end we are implementing the technology of zinc-finger nucleases, to help to conduct homologous recombination. Last, we are developing nanotools to label and track the cells in vivo, and study their cell biology in culture.

Relevant publications:

  • Daviaud N, Garbayo E, Sindji L, Martínez-Serrano A, Schiller PC, Montero-Menei CN. Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease. Stem Cells Transl Med. 2015 Jun;4(6):670-84. doi: 10.5966/sctm.2014-0139. Epub 2015 Apr 29. PMID:25890124
  • Ramos-Gómez M, Seiz EG, Martínez-Serrano A. Optimization of the magnetic labeling of human neural stem cells and MRI visualization in the hemiparkinsonian rat brain. J Nanobiotechnology. 2015 Mar 5;13:20. doi: 10.1186/s12951-015-0078-4. PMID:25890124
  • González-Sánchez HM, Monsiváis-Urenda A, Salazar-Aldrete CA, Hernández-Salinas A, Noyola DE, Jiménez-Capdeville ME, Martínez-Serrano A, Castillo CG. Effects of cytomegalovirus infection in human neural precursor cells depend on their differentiation state. J Neurovirol. 2015 Apr 8. [Epub ahead of print] PMID:25851778
  • Pino-Barrio MJ, García-García E, Menéndez P, Martínez-Serrano A. V-myc immortalizes human neural stem cells in the absence of pluripotency-associated traits. PLoS One. 2015 Mar 12;10(3):e0118499. doi: 10.1371/journal.pone.0118499. eCollection 2015. PMID:25764185
  • Martínez-Serrano A, Castillo CG, Courtois ET, García-García and Liste I (2011) Modulation of the generation of dopaminergic neurons from human neural stem cells by Bcl-XL. Mechanisms of action. Vitam. Horm. 87, 175-205.
  • García-García, E., Pino-Barrio, M.J., López-Medina, L., and Martínez-Serrano, A. (2012) Intermidiate progenitors are increased by lengthening of cell cycle through calcium signalling and p53 expression in human neural progenitors. Mol. Biol. Cell., 23, 1167-1180.
  • Fernández-Cabada, T., Sánchez-López de Pablo, C., Martínez-Serrano, A., del Pozo Guerrero, F. Serrano-Olmedo, J.J., Ramos-Gomez M (2012) Cell death induction in glioblastoma cell lines by hyperthermic therapy based on gold nanorods. International Journal of Nanomedicine 7, 1511-1523.
  • Ramos-Moreno, T., Castillo, C.G. and Martínez-Serrano, A. (2012) Long-term behavioral effects of functional dopaminergic neurons generated from human neural stem cells in the rat 6-OH-DA Parkinson's disease model. Effects of the forced expression of Bcl-XL. Behav. Brain Res., 232, 225-232.
  • Seiz, E.G., Ramos-Gómez, M., Courtois, E.T., Tønnesen, J., Kokaia, M., Liste I., and Martínez-Serrano, A., (2012) Human midbrain precursors activate the expected developmental genetic program and differentiate to functional A9 dopamine neurons in vitro. Short and Long term enhancement by Bcl-XL. Experimental Cell Research 318: 2446-59.


Doctoral theses:

Javier Gonzalez Lendínez (2011). Identification and analysis of suitable human ventral mesencephalic precursors of dopaminergic neurons for cell therapy research in Parkinson's Disease. Universidad Autónoma de Madrid. Co-director: Dra. Tania Ramos Moreno.

Emma Green (2012). The use of zinc-finger nucleases to track the generation of dopaminergic neurons from immortalised human ventral mesencephalic neural stem cells. Universidad de Keele. Co-directores: Alberto Martínez Serrano y Tania Ramos Moreno.